Patient-oriented, epidemiological and translational research present several challenges, including prolonged recruitment periods, logistical difficulties, high patient refusal rates, etc. The proposed K22 faculty transition award aims to a) address oral cancer etiology with an innovative research design that overcomes practical difficulties, b) provide career enhancement activities, and c) allow the applicant to expand on his research and develop a high quality, sustainable, translational research program in the field of genetic cancer epidemiology. The long-term scientific objective of the project is to achieve accurate quantitation of the oral cancer risk in the United States by applying novel genetic and epidemiological techniques. The genetic predisposition of human subjects to the development of oral premalignancy is not adequately understood. The applicant will conduct a nested case control investigation within the 51,529-member Health Professionals Follow-up Study to evaluate a) the role of the Insulin-like Growth Factor 2 Receptor gene (IGF2R) short tandem repeat polymorphisms in the early stages of oral carcinogenesis, controlling for confounding, b) the role of polymorphisms at glutathione-S-transferase T gene (GST-T), as well as dopamine transporter and receptor genes (DAT & DRD2) on the premalignancy risk, and c) evaluate the role of alcohol metabolizing genes (SNPs on ADH2 & ADH3) on the premalignancy risk. Strengths of the proposed plan is the utilization of recently-identified strong genetic risk factors in the research design and the participation of study subjects from the Health Professionals Follow up study (HPFS), a cohort uniquely suited for epidemiologic studies on the etiology of complex diseases. The nesting of the project within the HPFS allows for longitudinal evaluations of validated data, increased recruitment and sample size, high quality DNA availability and overall increased feasibility.